This invention relates in general to an improved formulation for a negative contrast agent adapted to be used with magnetic resonance imaging (MRI) and more particularly to agents that can be employed in the gastrointestinal (GI) track.
The use of contrast agents for MRI and, in particular, use of negative oral contrast agents for GI track identification in MRI are well known. Among the many agents that are known are those that are disclosed in U.S. Pats. No. 4,927,624 (the use of clay); 4,770,183 (the use of a particular size superparamagnetic metal oxide particles) and 5,069,216 (biologically degradable superparamagnetic metal oxides having less than a predetermined average diameter).
In general, applicant understands that the primary uses and investigation has focused on perflurocarbons and ferrite materials. Although these materials are effective in providing a good contrast, they are relatively expensive and they pose problems of toxicity.
Barium sulfate (barium) has been tried on at least an experimental basis as have various clays including, most significantly, bentonite. With a concentration of these materials that is acceptable to the patient, the contrast improvement is very limited. In order to get an optimum contrast improvement, the amount and concentration of barium or clay material required is unacceptable. It is not only difficult to ingest but causes an unacceptable amount of constipation.
Accordingly, it is a major purpose of this invention to provide an improved formulation for a negative image contrast agent for use with MRI that will avoid the previously known toxicity, palatability and constipation problems that occur with presently known agents.
It is another related purpose of this invention to provide the above object with an agent that has reasonable cost so as to facilitate its use in as wide a variety of applications as possible.
The U.S. Pat. No. 5,069,216, issued Dec. 3, 1991 provides a fairly extensive discussion of the technology in this art and need not be repeated here. The agents of concern are called negative contrast agents because they serve to decrease the signal intensity thereby resulting in image darkening. More particularly, in MRI, the images are produced on the trailing edge of a magnetic pulse when the hydrogen nuclei in tissue provide a signal when switching from a magnetized to a demagnetized state. The switch is called a relaxation switch and the time it takes is called a relaxation time period. Without going into the specific physics of it, there are two relaxation times, called T1 and T2 (respectively longitudinal relaxation time and transverse relaxation time). These two relaxation times T1 and T2 generate two different signals which provide two different images.
Indeed, every pulse sequence generates both T1 and T2 signals in a specific proportion. Those sequences generating substantially more T1 signal are referred to herein as T1 weighted pulse sequences which yield T1 weighted images. The converse applies with respect to those sequences generating a substantially larger T2 signal which yield T2 weighted images.
The image produced often lacks clear definition (contrast) because of comparable signals produced by adjacent tissues other than the organ or tissue of interest. That contrast agent which localizes or concentrates in a tissue serves to modify the magnetic properties of that tissue in which it concentrates and thus can provide a better contrast between that tissue and the surrounding tissue.
Negative contrast agents operate in three different ways to modify the magnetic properties of the tissue in which they are concentrated. These three ways are the following:
A. By increasing the magnetic susceptibility of the tissue. Superparamagnetic agents operate in this way and to a much lesser extent so does barium and clay. PA1 B. By decreasing proton density. This occurs by displacing water. This is how barium, perflurocarbons and gas work. PA1 C. By reducing the rotational mobility of the protons present. This is essentially how the clays work.
It is important to recognize that an optimum contrast agent is one which will provide an appropriate trade-off of three functional characteristics. These three functional characteristics are: (1) provides a marked contrast between the tissue of interest and the surrounding tissue, (2) has minimum adverse medical impact on the patient; and (3) is as acceptable as possible to a patient from the point of view of taste and comfort. An optimum contrast agent is one that does not hold its magnetic state in the absence of an employed magnetic field, is not toxic to the human body and does not require quantities which will cause discomfort such as constipation.
In addition, cost is a major factor in providing an agent which is to be used in a large number of procedures. Thus it is another object of this invention to obtain an optimum trade-off of the above three functional characteristics together with cost as a fourth parameter.